Aryloxypropanolamine β 3 adrenergic agonists

ABSTRACT

Compounds of the formula    &lt;IMAGE&gt;  I  and pharmaceutically acceptable salts thereof wherein: R1 to R9 are as defined herein and m is the integer 0 or 1. These compounds are beta 3 adrenergic receptor agonists and are useful, therefore for example, in the treatment of diabetes, obesity, gastrointestinal diseases and achalasia.

BRIEF DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula ##STR2##and pharmaceutically acceptable salts thereof. As used in formula I, andthroughout the specification, the symbols have the following meanings:

R¹, R² and R³ are independently hydrogen, hydroxy, alkoxy, nitro, amino,alkylsulfonylamino, acylamino, alkylsulfonyl, alkyl, cycloalkyl, phenyl,hydroxymethyl, cyano, aminocarbonyl, halogen or trifluoromethyl. Inaddition, two of the three substituents (R¹, R² and R³) may togetherwith the carbon atoms to which they are attached form a heterocycle.

R⁴, R⁵ and R⁶ are independently hydrogen, alkoxycarbonyl, carboxy,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkoxycarbonylmethyl, carboxymethyl, aminocarbonylmethyl,alkylaminocarbonylmethyl, dialkylaminocarbonylmethyl, hydroxy, alkoxy,di- or trifluoromethoxy, halogen, trifluoromethyl, cycloalkyl or alkyl.In addition, two of the three substituents (R⁴, R⁵ and R⁶) may togetherbe methylenedioxy or benzo such that they together with the benzene ringto which they are attached form naphthyl;

R⁷, R⁸ and R⁹ are independently hydrogen, alkoxycarbonyl, carboxy,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkoxycarbonylmethyl, carboxymethyl, aminocarbonylmethyl,alkylaminocarbonylmethyl, dialkylaminocarbonylmethyl, hydroxy, alkoxy,di- or trifluoromethoxy, halogen, trifluoromethyl, cycloalkyl or alkyl.In addition, two of the three substituents (R⁷, R⁸ and R⁹) may togetherbe methylenedioxy or benzo such that they together with the benzene ringto which they are attached form naphthyl; and

m is the integer 0 or 1; provided that when R¹ is hydrogen, then R² andR³ may not be halogen and alkyl, chloro and hydrogen, or acylamino andhydrogen.

Compounds of the formula I where the substituents are as defined aboveare novel compounds provided that: a) when m is zero and R⁴ to R⁹ areall hydrogen and two of the three substituents R¹, R² and R³ togetherwith the carbons to which they are attached form a heterocycle, theheterocycle must be other than a 2-hydroxypyridine or a3,4-dihydro-2-hydroxypyridine; and b) when m is zero and R¹ and R⁴ to R⁹are all hydrogen, then R² and R³ may not be 1 ) hydrogen andhydroxymethyl, 2) alkyl and alkyl, 3) alkyl and alkoxy, 4) alkoxy andalkoxy, or 5) chloro and chloro.

The compounds of formula I possess activity at the beta 3 adrenergicreceptor in mammals and are useful in the treatment of diabetes,obesity, gastrointestinal diseases and achalasia.

DESCRIPTION OF THE INVENTION

The present invention provides for compounds of formula I,pharmaceutical compositions employing such compounds and for methods ofusing such compounds. Listed below are definitions of various terms usedto describe the compounds of the instant invention. These definitionsapply to the terms as they are used throughout the specification (unlessthey are otherwise limited in specific instances) either individually oras part of a larger group.

The term "alkyl" refers to both straight and branched chain groupshaving 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl,butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl,4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl,dodecyl, the various branched chain isomers thereof, and the like.

The term "cycloalkyl" refers to saturated cyclic hydrocarbon groupscontaining 3 to 7 ring carbons.

The term "lower alkyl" as employed herein includes such alkyl groups asdescribed above containing I to 6 carbon atoms.

The term "alkoxy" refers to any of the above alkyl groups linked to anoxygen atom.

The term "lower alkoxy" refers to any of the above lower alkyl groupslinked to an oxygen atom.

The term "heterocycle" refers to 5- and 6-membered rings containing from1 to 3 heteroatoms. The heterocycle may be aromatic or non-aromatic, andthe heteroatoms may be oxygen, nitrogen, and sulfur. Examples ofsuitable heterocycles include furan, 2,3-dihydrofuran, pyrrole,2,3-dihydropyrrole, thiophene, 2,3-dihydrothiophene, oxazole, imidazole,thiazole, 1,2,3-triazole, 1,2,3-thiadiazole, pyridine and pyrimidine.The heterocycle may be optionally substituted by one or more of thefollowing groups: hydroxy, oxo, halogen, trifluoromethyl, cyano, amino,nitro, alkyl, alkylsulfonyl, and alkoxy. Examples of substitutedheterocycles include 2-nitrofuran, 2-chloropyrrole, 3-cyanopyrrole,2-(trifluoromethyl)thiophene, 2-methyloxazole, oxazolo-2-one,imidazol-2-one, 2-aminothiazole, 2-methoxythiazole,N-methylsulfonyl-1,2,3-triazole, 2-hydroxypyridine,3,4-dihydro-2-hydroxypyridine and uracil. Where these heterocycles areformed from two of the three substituents R¹, R² and R³ and the carbonatoms to which they are attached, there may result more than onepossible benzoheterocycle. All such isomers are contemplated. Forexample, the heterocycle pyridine may be incorporated in either aquinoline or an isoquinoline ring system.

The term "halogen" or "halo" refers to chlorine, bromine, fluorine oriodine.

The compounds of formula I can be converted to salts, in particularpharmaceutically acceptable salts using art recognized procedures. Thecompounds of formula I have a basic center, and they can form acidaddition salts. These are formed, for example, with strong inorganicacids, such as mineral acids for example sulfuric acid, phosphoric acidor a hydrohalic acid, with strong organic carboxylic acids, such asalkanecarboxylic acids of I to 4 carbon atoms which are unsubstituted orsubstituted, for example, by halogen, for example acetic acid, such assaturated or unsaturated dicarboxylic acids, for example oxalic,malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, suchas hydroxycarboxylic acids, for example ascorbic, glycolic, lactic,malic, tartaric or citric acid, such as amino acids, for exampleaspartic or glutamic acid, or such as benzoic acid, or with organicsulfonic acids, such as alkane- (of 1 to 4 carbon atoms) or arylsulfonicacids, for example methane- or p-toluenesulfonic acid. Correspondingacid addition salts can also be formed having, if desired, anadditionally present basic center. The compounds of formula I having atleast one acid group can form salts with bases. Suitable salts withbases are, for example, metal salts, such as alkali metal or alkalineearth metal salts, for example sodium, potassium or magnesium salts, orsalts with ammonia or an organic amine, such as morpholine,thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-loweralkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-,triethyl-, tributyl- or dimethylpropylamine, or a mono-, di- ortrihydroxy lower alkylamine, for example mono-, di- or triethanolamine.Internal salts may furthermore be formed. Salts which are unsuitable forpharmaceutical uses but which can be employed, for example, for theisolation or purification of free compounds I or their pharmaceuticallyacceptable salts, are also included.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.

It should be understood that the present invention includes prodrugforms of the compounds of formula I.

The compounds of the instant invention may be in the free or hydrateform, and may be obtained by methods exemplified by the followingdescriptions.

Compounds of formula I may be prepared by coupling compounds of formula##STR3## with a compound of formula ##STR4## by heating them togetheroptionally in the presence of a solvent such as ethanol or by the methoddescribed in R. K. Atkins et al., Tet. Lett., 27, 2451 (1986).

Compounds of formula II are available in optically active form byreacting an activated glycidyl alcohol such as (2S)-(+)-glycidyl3-nitrobenzenesulfonate with a phenoxide such as sodium phenoxide in anorganic solvent such as dimethylformamide as described in J. M. Klunderet al., J. Org. Chem., 54, 1295 (1989).

It is recognized that the required phenol ##STR5## may not always bereadily available. In many cases such phenols may be prepared from theanalogous benzaldehydes of formula ##STR6## or the acetophenones offormula ##STR7## by Baeyer-Villiger oxidation, for example withperacetic acid or m-chloroperoxybenzoic acid, followed by esterhydrolysis, for example with aqueous sodium hydroxide, or from theanalogous aryl bromide of formula ##STR8## or the aryl iodide of formula##STR9## by a variety of methods discussed in the series Compendium ofOrganic Synthetic Methods (John Wiley & Sons), Section 40.

The compounds of formula III may be prepared from any of threeprecursors, ketone IV, alcohol VI, or aldehydes VII or XI.

Compounds of formula III are prepared by fusion of a ketone of formula##STR10## with ammonium formate followed by heating with a strongmineral acid such as a 37% aqueous hydrochloric acid-methanol mixture orhydrogen chloride (gas) in methanol solution.

Alternatively, compounds of formula III may be prepared by condensationof the compounds of formula IV with O-alkyl- or O-benzylhydroxylaminesin a solvent such as a pyridine-ethanol mixture to form the oxime ethersof formula ##STR11## wherein R is alkyl or benzyl. Compounds of formulaV may be converted to racemic amines of formula III by reduction with,for example, diborane. Optically active amines of formula III, where mis 1, are available by reduction of compounds of formula V withborane-norephedrine adducts as described in Y. Sakito et al., Tet.Lett., 29, 223 (1988).

Additional methods for the preparation of compounds of formula III fromthe compounds of formula IV include:

1. Asymmetric reduction of the N-acyl hydrazone derivative of theketones IV followed by reduction of the resultant N-acyl hydrazine toprovide optically active amines of formula III where m is 1. Thesemethods are described in M. J. Burk et al., Tet., 50, 4399 (1994 ); and

2. Reductive amination of the ketones of formula IV with sodiumcyanoborohydride and ammonia as described in C. F. Lane, Synth., 135(1975) to provide the compounds of formula III.

Compounds of formula III are also available from alcohols of formula##STR12## These alcohols may be tosylated or converted to thecorresponding chloride or bromide by the methods discussed in the seriesCompendium of Organic Synthetic Methods (John Wiley & Sons), Section 138and then converted to the compounds of formula III by treatment withammonia in a solvent such as tetrahydrofuran or by sequential treatmentwith an azide source such as lithium azide in a solvent such as ethanolfollowed by a reducing agent such as triphenylphosphine.

Alternatively the alcohols of formula VI may be converted to thecorresponding azides directly by treatment with diphenylphosphoryl azideand 1,8-diazabicyclo [5.4.0] undec-7-ene as described in A. S. Thompsonet al., J. Org. Chem., 58, 5886 (1993). Subsequent reduction, forexample with triphenylphosphine then provides the compounds of formulaIII. Optically active compounds of formula III where m is 1 areavailable by this route when the corresponding alcohol startingmaterials are optically active.

The compounds of formula III are available in optically active form byreacting aldehydes of formula ##STR13## and optically activephenylglycinol to form the intermediate imines of formula ##STR14##

Addition of compounds of formula ##STR15## where X is chlorine, bromine,or iodine, after pretreatment with cerous chloride, to the iminesproduces adducts of formula ##STR16##

Chiral auxiliary cleavage by treatment with lead tetracetate followed bywarm aqueous hydrochloric or sulfuric acid gives the compounds offormula III. To prepare compounds of formula III where m is 0, compoundsof formula ##STR17## may also be used in place of VII and IX,respectively. These methods are described in M. J. Wu et al., J. Org.Chem. 56, 1340 (1991) and M. K. Mokhallalati et al., Synth. Commun., 23,2055 (1993).

Additional methods for the preparation of compounds of formula III fromcompounds of formula VII and XI include:

1. Addition of compounds of formula ##STR18## (where M is lithium orsodium or magnesium monochloride, monobromide or monoiodide) to theN-trimethylsilylaldimine of the compounds of formula VII using themethod described in D. J. Hart et al., J. Org. Chem., 48, 289 (1983).Likewise, compounds of formula III where m is 0 may also be preparedwith the compounds of formula ##STR19## 2. Formation of the imine of thecompounds of formula VII with 4-methoxyaniline, addition of compounds offormula XIII where M is lithium in the presence of a chiral ligand, andcleavage of the 4-methoxyphenyl group provides the amines III inoptically active form. These methods are described in I. Inoue, Tet.,50, 4429 (1994). Likewise, compounds of formula III where m is 0 mayalso be prepared with compounds of formula XI and XIV where M in XIV islithium.

The compounds of formula IV are commercially available or may beprepared by Friedel-Crafts acylation of a compound of formula ##STR20##with a compound of formula ##STR21## or where m is 0, of a compound offormula ##STR22## with a compound of formula ##STR23##

Typically, acid chlorides of formula XVI and XVIII may be prepared fromthe corresponding carboxylic acids by treatment with thionyl chloride oroxalyl chloride in methylene chloride solution, either optionally in thepresence of catalytic N,N-dimethyl-formamide.

Compounds of formula IV may also be prepared by oxidation, for examplewith Jones' reagent, of compounds of formula VI.

Alternatively, compounds of formula IV where m is 1 may be obtained fromcompounds of formula XVIII and compounds of formula ##STR24## where X'is chlorine or bromine following the procedures described in M. Iyoda etal., Tet. Lett., 26, 4777 (1985).

Compounds of formula VI are obtained by addition of a compound offormula XIII to a compound of formula VII or where m is 0, by additionof a compound of formula XIV, to a compound of formula XI.

Reduction of compounds of formula IV with a reducing agent such assodium borohydride in a solvent such as ethanol also provides alcoholsof formula VI. To prepare the optically active alcohols of formula VIwhere m is one, the ketone IV where m is one is reduced with a chiralreducing agent as described in D. J. Mathre et al., J. Org. Chem., 58,2880 (1993).

The aldehydes of formulas VII and XI are commercially available or areprepared from the analogous benzyl alcohols, benzoic acids, arylhalides, benzonitriles, benzyl halides, etc. by methods discussed in theseries Compendium of Organic Synthetic Methods (John Wiley & Sons).

Certain substituents R¹, R² and R³ may be incompatible with thesynthetic route outlined above. To prepare the compounds of formula Icontaining these substituents the following modifications may be used.

Where R¹, R² or R³ is hydroxyl, the compound of formula lI is preparedwith the hydroxyl group protected, for example, as a benzyl ortrialkylsilyl ether. After coupling of II with III, the protecting groupis removed to provide the compound of formula I. The installation andremoval of such protecting groups are discussed in Protective Groups inOrganic Synthesis by T. W. Greene (John Wiley & Sons).

Where R¹, R² or R³ is amino, the compound of formula I where thatsubstituent is nitro is prepared according to the synthetic methodologyoutlined above. This compound is then reduced to provide the compound offormula I bearing the amino group. Reduction of nitro groups to aminogroups may be carried out, for example, by hydrogenation over a catalystsuch as Raney Nickel in a solvent such as tetrahydrofuran or bytreatment with tin (II) chloride in a solvent such as ethyl acetate.

Where two of the three substituents R¹, R² and R³ together with thebenzene ring to which they are attached form a benzimidazole,benzimidazol-2-one, or benzotriazole, the compound of formula I wherethese two substituents are amino groups is prepared according to thesynthetic methodology outlined above. This diamino compound is thencarbonylated to provide the compound of formula I that is abenzimidazol-2-one. Such carbonylations may be carried out, for example,with phosgene in aqueous hydrochloric acid solution or with othercarbonylating agents such as triphosgene or 1,1'-carbonyldiimidazole.

To provide the compound of formula I that is a benzotriazole, thediamino compound is treated with nitrous acid, for example, by additionof sodium nitrite to a solution of the diamino compound in methanol,acetic acid and aqueous hydrochloric acid.

To provide the compound of formula I that is a benzimidazole the diaminocompound is treated with formic acid or triethyl orthoformate or withcarbon disulfide and barium hydroxide followed by hydrogenation overRaney Nickel. These and other benzimidazole formation methods arediscussed in Comprehensive Org. Chem., Volume IV, editors:chapter-(17.3) M. R. Grimmett; volume-P. G. Sammes; Series-D. Barton andW. D. Oilis.

Certain substituents R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ may be incompatible withthe synthetic route outlined above. To prepare the compounds of formulaI containing these substituents the following modifications may be used.

Where one of these substituents is hydroxyl, the compound of formula IIIis prepared with the hydroxyl group protected, for example, as a benzylor trialkylsilyl ether. After coupling of II with III, the protectinggroup is removed to provide the compound of formula I. The installationand removal of such protecting groups are discussed in Protective Groupsin Organic Synthesis by T. W. Greene (John Wiley & Sons).

Where one of these substituents is an alkoxycarbonyl, carboxy, oraminocarbonyl functional group, the compound of formula I where thatsubstituent is either of the other two of these functional groups may beprepared according to the synthetic methodology outlined above. This isthen converted to the desired compound of formula I. For example, if thedesired compound of formula I is substituted with a carboxy group, thenthe corresponding compound of formula I containing an alkoxycarbonyl oran aminocarbonyl group may be prepared and converted to the carboxycompound. Likewise, if the desired substituent is an aminocarbonylgroup, either a carboxy group or an alkoxycarbonyl group may serve asits precursor. Additionally, the compounds of formula I substituted byalkylaminocarbonyl or dialkylaminocarbonyl groups are available from thecompounds of formula I substituted by alkoxycarbonyl or carboxy groups.Analogously, the compounds of formula I substituted byalkoxycarbonylmethyl, carboxymethyl, or aminocarbonylmethyl groups maybe prepared from the compounds of formula I substituted by either of theother two of these functional groups, and the compounds of formula Isubstituted by alkylaminocarbonylmethyl or dialkylaminocarbonylmethylgroups are available from the compounds of formula I substituted byalkoxycarbonylmethyl or carboxymethyl groups. Numerous methods for theinterconversion of these functional groups are described in the seriesCompendium of Organic Synthetic Methods (John Wiley & Sons).

Alternatively, where one of the substituents R⁴, R⁵, R⁶, R⁷, R⁸ or R⁹ inthe desired compound of formula I contains an amide (amiocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylmethyl,alkylaminocarbonylmethyl, or dialkylaminocarbonylmethyl), thecorresponding amine III bearing that amide substituent is employed asdescribed above. The amine III may be prepared from an analogous amineIII in which that substituent contains an ester (alkoxycarbonyl oralkoxycarbonylmethyl) in place of the amide. The ester-containing aminemay be prepared by the routes outlined above; it may be converted to thecorresponding amide-containing amine by 1) protection of the basic aminogroup for example as the t-butoxycarbonyl derivative; 2) conversion ofthe ester to the amide; and 3) deprotection of the amino group.

In cases where one of the substituents R⁴, R⁵, R⁶, R⁷, R⁸ or R⁹ in amineIII is methoxycarbonylmethyl it is possible to prepare the amine IIIusing a cyanomethyl group as a protected form of themethoxycarbonylmethyl group. For example, to prepare the compound offormula III where m is one, R⁴ is p-CH₃ OCOCH₂, and R⁵, R⁶, R⁷, R⁸ andR⁹ are all hydrogen, one may begin with p-bromomethylbenzoic acid.Reaction with potassium cyanide in aqueous ethanol at reflux givesp-cyanomethylbenzoic acid, which is converted to the acid chloride(XVIII) and then, by reaction with benzyl bromide (XIX), to IV asdescribed above. Fusion of IV with ammonium formate followed by heatingin methanolic hydrogen chloride, as described above, not only effectsreductive amination, but also converts the cyanomethyl group to amethoxycarbonylmethyl group and the required compound III is obtained.

It is recognized that more than one of the synthetic modificationsuseful for the incorporation of certain substituents may besimultaneously employed.

In any of the above reactions, it may be necessary to protect certainsubstituents by using protecting groups as known by those skilled in theart.

Compounds of the formula I where the substituents are as defined aboveare novel compounds provided that: a) when m is zero and R⁴ to R⁹ areall hydrogen and two of the three substituents R¹, R² and R³ togetherwith the carbons to which they are attached form a heterocycle, theheterocycle must be other than a 2-hydroxypyridine or a3,4-dihydro-2-hydroxypyridine; and b) when m is zero and R¹ and R⁴ to R⁹are all hydrogen, then R² and R³ may not be 1) hydrogen andhydroxymethyl, 2) alkyl and alkyl, 3) alkyl and alkoxy, 4) alkoxy andalkoxy, or 5) chloro and chloro.

Preferred novel compounds of formula I are those where the substituentsare as defined above provided that: a) where two of the threesubstituents R¹, R² and R³ together with the carbons to which they areattached form a heterocycle, the heterocycle is other than a2-hydroxypyridine or a 3,4-dihydro-2-hydroxypyridine; b) when m is zeroand R¹ and R⁴ to R⁹ are all hydrogen, then R² and R³ may not be 1)hydrogen and hydroxymethyl, 2) hydrogen and aminocarbonyl, 3) alkyl andalkoxy, 4) chloro and alkoxy, 5) chloro and chloro, 6) alkoxy and alkoxyor 7) alkyl and alkyl; c) when R⁴ to R⁹ are all hydrogen or halogen andR¹ and R² are hydrogen, then R³ may not be hydrogen, phenyl or alkoxy;and d) when R¹ and R⁴ to R⁹ are all hydrogen, then R² and R³ may notboth be alkyl.

Preferred compounds of formula I are also those where the hydroxylstereocenter has the (S) configuration. Additional preferred compoundsof formula I are those where R¹, R⁴, R⁷ and R⁸ are hydrogen and m isone; and those where R¹, R⁴, R⁷, R⁸ and R⁹ are hydrogen and m is one.

The most preferred compounds of formula I are those where the hydroxylstereocenter has the (S) configuration, the amine stereocenter has the(R) configuration and m is one.

The present compounds of formula I have activity at the beta 3adrenergic receptor and are therefore useful, for example, in thetreatment of diabetes, obesity, gastrointestinal diseases (such asinflammatory bowel disease, irritable bowel syndrome, nonspecificdiarrhea, and peptic ulcer) and achalasia.

Thus a composition containing one (or a combination) of the compounds ofthis invention, may be administered to a species of mammal (e.g.,humans) suffering from diabetes, obesity, an intestinal hypermotilitydisorder or achalasia as treatment therefor.

A single dose, or two to four divided daily doses, provided on a basisof about 0.1 to 100 mg per kilogram of body weight per day, preferablyabout 1 to 15 mg per kilogram of body weight per day is appropriate. Thesubstance is preferably administered orally, but intranasal, transdermaland parenteral routes such as the subcutaneous, intramuscular,intravenous or intraperitoneal routes can also be employed.

The compounds of this invention can also be formulated in combinationwith beta₁ /beta₂ adrenergic blockers such as propranolol and nadolol orstimulants such as salbutamol.

The compounds of formula I can be formulated for use in compositionssuch as tablets, capsules or elixirs for oral administration, in sterilesolutions or suspensions for parenteral or intranasal administration, orin transdermal patches. About 10 to 500 mg of a compound of formula I iscompounded with a physiologically acceptable vehicle, carrier,excipient, binder, preservative, stabilizer, flavor, etc., in a unitdosage form as called for by accepted pharmaceutical practice. Theamount of active substance in these compositions or preparations is suchthat a suitable dosage in the range indicated is obtained.

Based on the literature, it is expected that these compounds may beuseful for other indications such as treatment of depression and stress,regulation of intraocular pressure, treatment of conditions associatedwith increased protein breakdown such as during convalescence aftersurgery, treatment of hypertriglyceridemia, hypercholesterolemia,atherosclerotic and cardiovascular diseases, and for increasing highdensity lipoprotein levels. In addition, it is expected that thesecompounds may be useful as feed additives for fattening or improvingweight gain or increasing lean body mass in animals and may therefore beused to decrease birth mortality and increase post-natal survival ratesin animals.

In addition, based on the literature, compounds of formula I areexpected to be useful for improving healing and preventing stomachulcers (K. Kuratani et al., J. Pharmacol. Exp. Ther. 270, 559 (1994)).The compounds of formula I are also expected to be useful for regulatingcore temperature.

The following examples and preparations describe the invention and areillustrative rather than limiting. It should be understood that theremay be other embodiments which fall within the spirit and scope of theinvention as defined by the claims appended hereto.

EXAMPLE 1 (S)-1-[[Bis(4-methoxyphenyl)methyl]amino]-3-phenoxy-2-propanol##STR25## A. (S)-(Phenoxymethyl)oxirane

The title compound was prepared according to the methods described in J.M. Klunder et al., J. Org. Chem., 54, 1295 (1989). The ee of the titlecompound was shown to be 99.2% by chiral HPLC analysis. Its precursor((2S)-(+)-glycidyl 3-nitrobenzenesulfonate) was recrystallized fourtimes from ethanol to 99.8% ee.

B. (S)-1-[[Bis(4-methoxyphenyl)methyl]amino]-3-phenoxy-2-propanol

1. 4,4'-Dimethoxydiphenylmethylamine

The title compound was prepared according to Y. Ito et al., Tetrahedron,45, 5767 (1989).

2. (S)-1-[[Bis(4-methoxyphenyl)methyl]3mino]-3-phenoxy-2-propanol

To the title I compound (m.w. 243, 340 mg, 1.4 mmol, 1.6 equiv.) at roomtemperature under argon was added N-(trimethylsilyl)acetamide (m.w. 131,197 mg, 1.5 mmol, 1.7 equiv.). The resulting solution was stirred atroom temperature for two hours. To the mixture was then added the titleA compound (m.w. 150, 135 mg, 0.9 mmol). The resulting solution washeated for two days at 65°-70° C., then for three days at 180° C. Themixture was cooled to room temperature and diluted with ethyl acetate(˜20 mL). About 15 g of chipped ice and 4 mL conc. hydrochloric acidwere added. This mixture was stirred for four hours, allowing the ice tomelt. The mixture was basified to pH 12 by addition of 1M aq. sodiumhydroxide. The ethyl acetate layer was removed, and the aqueous layerwas then extracted three times with methylene chloride (100 mL). Thevarious organic extracts were combined, dried over sodium sulfate, andthen concentrated to a thick oil, which was purified by silica gelchromatography eluting with 2% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride to produce 232 mg of the titlecompound as a white powder (66% yield).

TLC: R_(f) =0.35 in 5% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride, p-anisaldehyde stain, UV.

MS: (M+H)⁺ at 394.

EXAMPLE 2(2S)-1-[[1-(3,4-Dimethoxyphenyl)-2-phenylethyl]amino]-3-phenoxy-2-propanol,trifiuoroacetate (1:1) salt ##STR26## A.1-(3,4-Dimethoxyphenyl)-2-phenylethylamine

The title compound was prepared according to I.P.G. Nerlekar et al., J.Karnatak Univ., 2, 58 (1957), abstracted by Chemical Abstracts 53:14051.

B.(2S)-1-[[1-(3,4-Dimethoxyphenyl)-2-phenylethyl]amino]-3-phenoxy-2-propanol,trifiuoroacetate (1:1) salt

The title compound was prepared from the title A compound (m.w. 257, 500mg, 1.9 mmol, 1.9 equiv.), N-(trimethylsilyl)acetamide (m.w. 131, 275mg, 2.1 mmol, 2.1 equiv.), and the title A compound of Example 1((S)-(phenoxymethyl)oxirane: m.w. 150, 150 mg, 1.0 mmol) according tothe procedures described for the preparation of the title 2 compound ofstep B of Example I with the following modifications. In this caseheating was carried out for three days at 65°-70° C. After silica gelchromatography eluting with 5% (10% cone. aq. ammoniumhydroxide/methanol)/methylene chloride, the chromatographed product wasdissolved in ether (˜30 mL) and then trifiuoroacetic acid (m.w. 114, d1.5, 0.230 mL, 0.34 g, 3.0 retool, 3.0 equiv.) was added. The solutionwas then coevaporated several times with toluene, then with methylenechloride, and finally with ether. This produced 340 mg of the titlecompound as a white powder (64% yield).

TLC: R_(f) =0.3 in 5% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride, p-anisaldehyde stain, UV.

MS: (M+H)⁺ at 408.

EXAMPLE 3(2S)-1-[[1-(3,4-Dimethoxyphenyl)-2-phenylethyl]amino]-3-(4-fiuorophenoxy)-2-propanol,trifiuoroacetate (1:1) salt ##STR27## A.(S)-[(4-Fluorophenoxy)methyl]oxirane

The title compound was prepared following the procedures described forthe preparation of the title A compound of Example 1((S)-(phenoxymethyl)oxirane) except using p-fluorophenol as a startingmaterial. The title compound was derived from chiral precursor of 99.86%ee (chiral HPLC analysis).

TLC: R_(f) =0.9 in 5% ethyl acetate/hexane, p-anisaldehyde stain, UV.

¹³ C NMR (67.8 MHz, CDCl₃) δ: 149.0, 141.2, 127.1, 120.2, 107.6, 69.6,50.0, 44.5.

B.(2S)-1-[[1-(3,4-Dimethoxyphenyl)-2-phenylethyl]-amino]-3-(4-fluorophenoxy)-2-propanol,trifluoroacetate (1:1) salt

To 1-(3,4-dimethoxyphenyl)-2-phenylethylamine (m.w. 257,500 mg, 1.9mmol, 1.9 equiv.) at room temperature under argon was addedN-(trimethylsilyl)acetamide (m.w. 131, 275 mg, 2.1 mmol, 2.1 equiv.).The mixture was stirred as a melt at 60° C. for two hours. To themixture was then added the title A compound (m.w. 168, 168 mg, 1.0mmol). The resulting solution was heated for three days at 100° C. Themixture was cooled to room temperature and diluted with ethyl acetate(˜10 mL). About 10 mL of chipped ice and 4 mL conc. hydrochloric acidwere added. This mixture was stirred for four hours, allowing the ice tomelt. The mixture was basified to pH 12 by addition of 1M aq. sodiumhydroxide. The ethyl acetate layer was removed, and the aqueous layerwas then extracted four times with methylene chloride (100 mL). Thevarious organic extracts were combined, dried over sodium sulfate, andthen concentrated to a thick oil, which was purified by silica gelchromatography eluting with 5% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride. The chromatographed product wasdissolved in ether (˜30 mL) and then trifiuoroacetic acid (m.w. 114, d1.5, 0.230 mL, 0.34 g, 3.0 mmol, 3.0 equiv.) was added. The solution wasthen coevaporated several times with toluene, then with methylenechloride, and finally with ether. This produced 340 mg of the titlecompound as a white powder (63% yield).

MS: (M+H)⁺ at 426.

EXAMPLE 4(2S)-3-([1,1'-Biphenyl]-2-yloxy)-1-[[1-(3,4-dimethoxyphenyl)-2-phenylethyl]smino]-2-propanol,trifluoroacetate (1:1) salt ##STR28## A.(S)-[([1,1'-Biphenyl]-2-yloxy)methyl]oxirane

Prepared from o-phenylphenol in >62% yield using procedures described inJ. M. Klunder et al., J. Org. Chem., 54, 1295 (1989). The precursor tothe title compound, (2S)-(+)-glycidyl 3-nitrobenzenesulfonate wasrecrystallized four times from ethanol to 99.8% ee (determined by chiralHPLC analysis). The title compound was shown to be 99.0% ee by chiralHPLC analysis.

TLC: R₁ =0.5 in 25% ethyl acetate/hexane, p-anisaldehyde stain, UV.

¹³ C NMR (CDCl₃) δ: 155, 148, 132, 129, 128, 127 126, 121, 113, 69, 50,

B. (2S)-3-([1,1'-Biphenyl]-2-yloxy)-1-[[1-(3,4-dimethoxyphenyl)-2-phenylethyl]amino]-2-propanol,trifluoroacetate (1:1) salt

The title compound was prepared according to the procedures describedfor the preparation of the title B compound of Example 3, but using thetitle A compound (m.w. 226, 226 mg, 1.0 mmol). In this case the productwas purified by silica gel chromatography eluting with 3%methanol/methylene chloride. Some product was left behind in mixedfractions. The purified product was then dissolved in a few millilitersof ether and treated with trifiuoroacetic acid (m.w. 114, 125 mg, 1.1mmol). The resulting solution was coevaporated several times withtoluene to remove excess trifiuoroacetic acid, then several times withmethylene chloride. Trituration with ether produced 210 mg of the titlecompound as a pale yellow solid (34% yield (corrected for 4% impurity)).

MS: (M+H)⁺ at 484.

EXAMPLE 5 (2S)-1-[[1-(3,4-Dimethoxyphenyl)-2-phenylethyl]amino]-3-(4-hydroxyphenoxy)-2-propanol##STR29## A. (S)-[[4-(Phenyhnethoxy)phenoxy]methyl]oxirane

Made following procedures described for the preparation of the title Acompound of Example I ((S)-(phenoxymethyl)oxirane) except using4-benzyloxyphenol as a starting material. The title compound was derivedfrom chiral precursor of 99.86% ee (chiral HPLC analysis).

TLC: R_(f) =0.7 in 30% ethyl acetate/hexane, p-anisaldehyde stain, UV.

¹³ C NMR (67.8 MHz, CDCl₃) δ: 153, 154, 137.1, 128.5, 127.8, 127.4,115.7, 115.6, 70.5, 69.4, 50.2, 44.6.

B.(2S)-1-[[1-(3,4-Dimethoxyphenyl)-2-phenylethyl]amino]-3-[4-(phenylmethoxy)phenoxy]-2-propanol

The title compound was prepared according to the procedures describedfor the preparation of the title B compound of Example 3 but using thetitle A compound (m.w. 256, 256 mg, 1.0 mmol). In this case the titlecompound was chromatographed eluting with 3% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride. The product, a yellow oil, wasnot salted.

TLC: R_(f) =0.5 in 3% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride, p-anisaldehyde stain, UV.

¹³ C NMR (67.8 MHz, CDCl3) δ: 154, 153, 148, 147, 138.5, 135, 134,129.2, 128.3, 128.2, 127.7, 127.3, 126.2, 119.2, 115.6, 115.3, 110.8,109.9, 71, 70.4, 69, 68, 63, 64, 55.6, 49, 50, 45.1.

C.(2S)-1-[[1-(3,4-Dimethoxyphenyl)-2-phenylethyl]-amino]-3-(4-hydroxyphenoxy)-2-propanol

To a solution of the title B compound (m.w. 513, 100 mg, 0.19 mmol) inmethanol (2 mL) at room temperature under argon was added acetic acid(glacial, 17.5M, 0.217 mL, 3.8 mmol, 20 equiv.) and 10% Pd/C (50 mg).The mixture was sparged with hydrogen for 10-15 minutes, then maintainedunder a hydrogen balloon for one and one half hours. The catalyst wasfiltered off and the filtrate was concentrated and chromatographed onsilica gel eluting with 15% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride. The title compound was isolatedin 95% purity as 60 mg of light brown solid (71% yield (corrected for 5%impurity)) after trituration with ether.

TLC: R_(f) =0.3 in 20% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride, p-anisaldehyde stain, UV.

MS: (M+H)⁺ at 424.

EXAMPLE 6 (2S)-1-[[1-(3,4-Dimethoxyphenyl)-2-phenylethyl]amino]-3-(2-hydroxyphenoxy)-2-propanol##STR30## A. (S)-[[2-(Phenylmethoxy)phenoxy]methyl]oxirane

Made in 63% yield by the method described for the title A compound ofExample I ((S)-(phenoxymethyl)oxirane), except using 2-benzyloxyphenolas the starting material. The title compound was derived from chiralprecursor of 99.86% ee (chiral HPLC analysis).

TLC: R_(f) =0.5 in 30% EtOAc/hexane, p-anisaldehyde stain, UV.

B.(2S)-1-[[1-(3,4-Dimethoxyphenyl)-2-phenylethyl]amino]-3-[2-(phenylmethoxy)phenoxy]-2-propanol

The title compound was prepared according to the procedures describedfor the preparation of the title B compound of Example 3 but using thetitle A compound. In this case the title compound was purified by silicagel chromatography eluting with 2% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride. The product, an oil, was notsalted.

TLC: R_(f) =0.3 in 3% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride, p-anisaldehyde stain, UV.

C. (2S)-1-[[1-(3,4-Dimethoxyphenyl)-2-phenylethyl]-amino]-3-(2-hydroxyphenoxy)-2-propanol

To a solution of the title B compound (m.w. 513, 550 mg impure, ˜415 mgnet, -0.8 mmol) in methanol (5 mL) at room temperature under argon wasadded acetic acid (glacial, 17.5 M, 0.183 mL, 3.2 mmol, ˜4 equiv.) and10% Pd/C (70 mg). The mixture was sparged with hydrogen for 10-15minutes, then maintained under a hydrogen balloon for five hours. Atthis point 20 mg more catalyst was added and the sparging repeated. Themixture was then maintained under 1 atm hydrogen for eight hours, atwhich point the reaction was nearly complete by TLC. The catalyst wasfiltered off and the filtrate was concentrated and chromatographed onsilica gel eluting with 2% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride. The title compound was isolatedas 50 mg of white powder after trituration with ether (15% isolatedyield--a large amount of material was left behind in mixed fractions).

TLC: R_(f) =0.5 in 10% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride, p-anisaldehyde stain, UV.

MS: (M+H)⁺ at 424.

EXAMPLE 7(2S)-1-[[1-(3,4-Dimethoxyphenyl)-2-phenylethyl]amino]-3-(3-hydroxyphenoxy)-2-propanol##STR31## A. (S)-[[3-(Phenylmethoxy)phenoxy]methyl]oxirane

Made in 51% yield by the method described for the title A compound ofExample 1 ((S)-(phenoxyrnethyl)oxirane) except using 3-benzyloxyphenol(made as described in Ponpipom, M. M., et al., J. Med. Chem., 30, 136(1987)) as the starting material. The title compound was derived fromchiral precursor of 99.86% ee (chiral HPLC analysis).

TLC: R_(f) =0.8 in 30% ethyl acetate/hexane, p-anisaldehyde stain, UV.

¹³ C NMR (67.8 MHz, CDCl3) δ: 160, 159, 136.8, 129.9, 128.5, 127.9,127.5, 107.6, 107.4, 102.0, 70.0, 68.7, 50.0, 44.7.

B.(2S)-1-[[1-(3,4-Dimethoxyphenyl)-2-phenylethyl]-amino]-3-[3-(phenylmethoxy)phenoxy]-2-propanol

The title compound was prepared according to the procedures describedfor the preparation of the title B compound of Example 3 but using thetitle A compound. In this case the title compound was purified by silicagel chromatography eluting with 2% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride. The product, an oil, was notsalted.

TLC: R_(f) =0.3 in 5% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride, p-anisaldehyde stain, UV.

C. (2S)-1-[[1-(3,4-Dimethoxyphenyl)-2-phenylethyl]-amino]-3-(3-hydroxyphenoxy )-2- propanol

To a solution of the title B compound (m.w. 513, 388 mg, 0.76 mmol) inmethanol (5 mL) at room temperature under argon was added acetic acid(glacial, 17.5M, 0.087 mL, 1.5 mmol, ˜2 equiv.) and 10% Pd/C (100 mg).The mixture was sparged with hydrogen for 10-15 minutes, then maintainedunder a hydrogen balloon for four hours. At this point 120 mg morecatalyst was added and the sparging was repeated. The mixture was thenmaintained under 1 atm hydrogen for six hours, at which point thereaction was complete by TLC. The catalyst was filtered off and thefiltrate was concentrated and chromatographed on silica gel eluting witha stepwise gradient of 1-5% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride. The title compound was isolatedas 150 mg of white powder after trituration with ether (47% yield).

TLC: R_(f) =0.5 in 10% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride, p-anisaldehyde stain, UV.

MS: (M+H)⁺ at 424.

EXAMPLE 8(2S)-1-(4-Amino-3-nitrophenoxy)-3-[[1-(3,4-dimethoxyphenyl)-2-phenylethyl]amino]-2-propanol##STR32## A. (S)-[(4-Amino-3-nitrophenoxy)methyl]oxirane

Made in 45% yield by the method described for the title A compound ofExample 1 ((S)-(phenoxymethyl)oxirane) except using4-amino-3-nitrophenol as a staring material. The title compound wasderived from chiral precursor of 99.86% ee (chiral HPLC analysis).

TLC: R_(f) =0.8 in 5% methanol/methylene chloride, p-anisaldehyde stain,UV.

B.(2S)-1-(4-Amino-3-nitrophenoxy)-3-[[1-(3,4-dimethoxyphenyl)-2-phenylethyl]amino]-2-propanol

The title compound was prepared according to the procedures describedfor the preparation of the title B compound of Example 3 but using thetitle A compound. In this case the title compound was purified by silicagel chromatography eluting with 2% methanol/methylene chloride. Thetitle compound, a dark orange powder, was not salted.

TLC: R_(f) =0.2 in 2% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride, p-anisaldehyde stain, UV.

MS: (M+H)⁺ at 468.

EXAMPLE 9 (2S)-1-(1H-Benzotriazol-5-yloxy)-3-[[1-(3,4-dimethoxyphenyl)-2-phenylethyl]amino]-2-propanol##STR33## A.(2S)-1-(3,4-Diaminophenoxy)-3-[[1-(3,4-dimethoxyphenyl)-2-phenylethyl]amino]-2-propanol,trihydrochloride

A slurry of W-6 Raney Nickel in water (6.6 g) was washed five times withwater, five times with isopropanol, and five times with tetrahydrofuran(freshly distilled from potassium benzophenone ketyl), and then placedunder argon at room temperature. To this slurry was added the titlecompound of Example 8((2S)-1-(4-Amino-3-nitrophenoxy)-3-[[1-(3,4-dimethoxyphenyl )-2-phenylethyl]amino]-2-propanol: m.w. 467, 770 mg, 1.6 mmol) as asolution in tetrahydrofuran (to total 24 mL of tetrahydrofuran). Themixture was sparged with hydrogen for 10-15 minutes, and then maintainedunder 1 atm hydrogen for five hours. The supernatant was then pipettedinto a flask containing ˜1M aq. hydrochloric acid (4.8 mL, ˜4.8 mmol).The resulting solution was concentrated to remove tetrahydrofuran andthen lyophilized to 410 mg of orange powder, which was shown by NMR tobe ˜60% pure title compound (28% corrected yield). Note: the titlecompound is unstable as the free base.

TLC (as free base): R_(f) =0.45 in 10% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride, p-anisaldehyde stain, UV.

B.(2S)-1-(1H-Benzotriazol-5-yloxy)-3-[[1-(3,4-dimethoxyphenyl)-2-phenylethyl]amino]-2-propanol

To a solution of the title A compound (m.w. 547, 200 mg, ˜60% pure, ˜120mg net, ˜0.22 mmol) in water (1.0 mL) and acetic acid (0.1 mL) at 0° Cunder argon was added NaNO₂ (1.0M aq., 0.24 mL, 0.24 mmol, 1 equiv.).The mixture was allowed to warm to room temperature. The startingmaterial was consumed after fifteen minutes reaction time as judged byanalytical HPLC. The reaction was quenched by addition of sodiumhydroxide (1.0M, 0.48 mL, 0.48 retool, 2.0 equiv.) The reaction solutionwas coevaporated several times with toluene and then with methylenechloride, combined with material from an earlier run, and thenchromatographed on silica gel eluting with 5% (10% conc. aq. ammoniumhydroxide/methanol)/methylene chloride. The title compound was isolatedas 10 mg of tan powder. The title compound was not stable to thechromatography conditions used.

MS: (M+H)⁺ at 449.

EXAMPLE 10(2S)-1-(2-Amino-3-nitrophenoxy)-3-[[1-(3,4-dimethoxyphenyl)-2-phenylethyl]amino]-2-propanol##STR34## A. (S)-[(2-Amino-3-nitrophenoxy)methyl oxirane

See J. M. Klunder et al., J. Org. Chem., 54, 1295 (1989) for thepreparation of chiral aryl glycidyl ethers and F. Aigbirhio et al., Tet.Asymmetry, 3,539 (1992) for a preparation of the title compound.

Under argon at room temperature 2-amino-3-nitrophenol (1.03 g, 6.68mmol) was dissolved in dry dimethylformamide (20 mL) with stirring. Tothe resulting red solution was added carefully 60% sodium hydride oildispersion (0.29 g unwashed, 0.17 g net, 7.25 mmol) which caused gasevolution, a mild exotherm, and a color change to deep purple. After onehour (2S)-(+)-glycidyl 3-nitrobenzenesulfonate (1.60 g, 6.18 mmol, 99.8%ee) was added. After four hours satd. aq. ammonium chloride solution(about 25 mL) was carefully added to quench excess sodium hydride. Waterwas added to dissolve precipitated solid, and the mixture was extractedfour times with diethyl ether. After drying over anhydrous sodiumsulfate, the combined organic layers were evaporated and thencoevaporated with toluene to remove residual dimethylformamide. Flashchromatography (silica gel, 0.5% to 1.0% methanol in methylene chloridestepwise gradient) was performed to isolate pure title compound (0.54 g,42% yield) as an orange solid. The optical purity of the title compoundwas 99.1% ee as determined by chiral HPLC (Chiracel OD column,hexane/2-propanol/diethylamine 85:15:0.1 eluant).

TLC (50% ethyl acetate in hexane-anisaldehyde, UV) R_(f) :2-amino-3-nitrophenol 0.50 (2S)-(+)-glycidyl 3-nitrobenzenesulfonate0.35 the title compound 0.43

¹³ C NMR (67.8 MHz in CDCl₃) δ: 146.9, 137.2, 131.8, 118.2, 115.3,114.4, 70.4, 49.8, 44.5.

B.(2S)-1-(2-Amino-3-nitrophenoxy)-3-[[1-(3,4-dimethoxyphenyl)-2-phenylethyl]mnlno]-2-propanol

In an oven-dried flask under argon a mixture of racemic1-(3,4-dimethoxyphenyl)-2-phenylethylamine (0.37 g, 1.44 mmol) andN-(trimethylsilyl)acetamide (0.23 g, 1.76 mmol) was melted and stirredat 90° C. for two hours. To this was added the title A epoxide (0.16 g,0.76 mmol) and the homogeneous mixture was heated at 103°118° C. for 20hours. After cooling to room temperature, about 20 mL each of ethylacetate and 6M aq. hydrochloric acid were added, and after stirring forabout ten minutes, a homogeneous mixture had formed. After two to fourhours addition of several volumes of ethyl acetate produced a mixture oftwo layers. Aq. sodium hydroxide (1.0M) was added until the mixture wasbasic. Ice was added to cool the mixture and the organic layer wasseparated. Four further extractions with methylene chloride wereperformed, and the organic layers were combined, dried over anhydroussodium sulfate, and evaporated. Flash chromatography (silica gel, 2%methanol in methylene chloride), provided the title compound (0.30 g,84% yield) as an orange solid foam.

TLC (5% [10% cone. aq. NH3 in methanol] in methylenechloride-anisaldehyde, UV) R_(f) :1-(3,4-dimethoxyphenyl)-2-phenylethylamine 0.30 the title A compound0.89 silylated title B compound intermediate 0.80 the title B compound0.36

MS by chemical ionization: (M+H)⁺ @468 and M.⁻ @467.

EXAMPLE 11(2S)-1-(2,3-Dimninophenoxy)-3-[[1-(3,4-dimethoxyphenyl)-2-phenylethyl]amino]2-propanol##STR35##

At room temperature 50% Raney Nickel/water slurry (0.6 g) was dried bytwice adding 2-propanol, stirring, and removing the supernatant afterthe Raney Nickel was allowed to settle. The 2-propanol was thenexchanged out for freshly distilled tetrahydrofuran by the same methodusing tetrahydrofuran five times. About one fifth of the resulting RaneyNickel/tetrahydrofuran slurry was then added to a stirring solution ofthe title compound of Example 10((2S)-1-(2-Amino-3-nitrophenoxy)-3-[[1-(3,4-dimethoxyphenyl)-2-phenylethyl]amino]-2-propanol:101 mg, 0.22 mmol) in dry tetrahydrofuran (4 mL) at room temperature.The mixture was sparged with hydrogen for five minutes before placingunder a hydrogen balloon for three hours. Disappearance of the originalyellow color coincided with complete consumption of starting material byTLC. The mixture was filtered through a short plug of silica gel elutingwith tetrahydrofuran. The eluant was evaporated to a gum, which uponcoevaporation with diethyl ether became a white solid, the titlecompound (0.09 g, 94% yield).

TLC (10% [10% cone. aq. NH₃ in methanol] in methylene chloride-anisaldehyde, UV) R_(f) : the title compound of Example 10 0.51 thetitle compound of Example 11 0.32

MS by chemical ionization: (M+H)⁺ @438.

EXAMPLE 12(2S)-1,3-Dihydro-4-[3-[[1-(3,4-dimethoxyphenyl)-2-phenylethyl]amino]-2-hydroxypropoxy]-2H-benzimidazol-2-one##STR36##

See U.S. Pat. No. 4,346,093 for the synthesis of a relatedbenzimidazolone by this method.

At room temperature phosgene gas was passed over a stirring solution ofthe title compound of Example 11((2S)-1-(2,3-Diaminophenoxy)-3-[[1-(3,4-dimethoxyphenyl)-2-phenylethyl]amino-2-propanol: 0.05 g, 0.11 mmol)in approximately0.2M aq. hydrochloric acid solution (approximately 5 mL) for one hour. Awhite precipitate formed. The mixture was then allowed to stand openovernight. The mixture was made basic by addition of 1.0M aq. sodiumbicarbonate solution. After brine was added, the mixture was extractedfour times with methylene chloride/ethyl acetate (3:1). The combinedorganic extracts were dried over anhydrous sodium sulfate and evaporatedto a gum, which upon coevaporation with diethyl ether became anoff-white solid, nearly pure desired product (59 mg, about 80% yield).To remove trace impurities, this material was flash chromatographed(silica gel, 0% to 15% [10% conc. aq. NH₃ in methanol] in methylenechloride, stepwise gradient) and, by coevaporation with diethyl ether,made into a white solid, the title compound.

TLC (10% [10% conc. aq. NH₃ in methanol] in methylene chloride-anisaldehyde, UV) R_(f). the title compound of Example 11 0.28 the titlecompound of Example 12 0.25

MS by chemical ionization: (M+H)⁺ @464 and (M-H)⁻ @462.

EXAMPLE 13(2S)-1-(1H-Benzotriazol-4-yloxy)-3-[[1-(3,4-dimethoxyphenyl)-2-phenylethyl]amino]-2-propanol##STR37##

See U.S. Pat. No. 4,346,093 for the synthesis of a related benzotriazoleby this method.

Impure, air-stable trihydrochloride salt of the title compound ofExample 11((2S)-1-(2,3-Diaminophenoxy)-3-[[1(3,4-dimethoxyphenyl)-2-phenylethyl]amino]-2-propanol)was prepared by dissolving impure title compound of Example 11 inmethanol at room temperature, adding 1.00M aq. hydrochloric add solution(3.3 equiv.), rotoevaporating, and then lyophilizing to obtain a solid.A solution of this material (0.06 g gross, 0.11 mmol net) in water (0.2mL) and acetic acid (0.05 mL) was cooled to 0° C. Upon addition of 1.0Maq. sodium nitrite solution (0.12 mL, 0.12 mmol), a precipitate formed.Additional water (0.2 mL) and methanol (0.5 mL) were added, and themixture was warmed to room temperature to dissolve all solids. TLCindicated complete reaction. After addition of 1.0M aq. sodium hydroxidesolution (0.24 mL), the mixture was coevaporated with methanol andtoluene to remove acetic acid and water. The residue was flashchromatographed (silica gel, 5% [10% conc. aq. NH₃ in methanol]inmethylene chloride) and coevaporation with diethyl ether gave, as anoff-white solid, the title compound (29 mg, 59% yield).

TLC (10% [10% conc. aq. NH₃ in methanol] in methylene chloride-anisaldehyde, UV) R_(f). the title compound of Example 11 0.27 the titlecompound of Example 13 0.25

MS by chemical ionization: (M+H)⁺ @449.

EXAMPLE 14 (2S)-1-[(1,2-Diphenylethyl)amino]-3-phenoxy-2-propanol,monohydmchloride ##STR38##

Under argon a mixture of the title A compound of Example 1((S)-(phenoxymethyl)oxirane; optical purity of 99.2% ee; 0.20 g, 1.3mmol) and 1,2-diphenylethylamine (0.43 g, 2.2 mmol) was heated to 135°C. and stirred for 2.5 hours. After cooling to room temperature themixture was flash chromatographed (silica gel, 0.5% to 0.75% [10% conc.aq. NH_(3/) MeOH]/CH₂ Cl₂ stepwise gradient) to provide the free base ofthe title compound as an oil. A solution of the free base in diethylether was prepared, and HCl gas was passed over the solution untilinsoluble oil stopped forming at the surface. The oil soon solidified.The solid was broken up and filtered, washing with ether. After dryingunder vacuum, the title compound was obtained as a white solid (0.39 g,78% yield).

TLC (2.5% [10% conc. aq. NH₃ in MeOH] in CH₂ Cl₂ -anisaldehyde, UV)Rf.(S)-(phenoxymethyl)oxirane 0.86 1,2-diphenylethylamine 0.17 the titlecompound 0.35

MS by electrospray ionization: (M+H)⁺ @348.

EXAMPLE 15(2S)-1-[[1-[4-(Difluoromethoxy)phenyl]-2-(4-fluorophenyl)ethyl]mnino]-3-phenoxy-2-propanol,monohydrochloride ##STR39## A. 4-(Difluoromethoxy)benzoic acid

Difiuorochloromethane was bubbled through a 75° C. i-PrOH (100 mL)solution containing commercially available methyl 4-hydroxybenzoate (7.5g, 5.0 mmol) and t-BuOK (5.6 g, 5 mmol). After two hours, 4 additional gof t-BuOK was added and the reaction continued two hours. The reactionwas diluted with H₂ O and extracted with EtOAc (3×). The organic phaseswere washed with H₂ O (3×), brine, dried over Na₂ SO₄ and concentratedto yield 12 g of methyl 4-difluoromethoxybenzoate as an oil. The crudemethyl 4-difluoromethoxybenzoate was refluxed two hours in 2:1MeOH/H₂ Ocontaining KOH (3.4 g, 61 mmol) followed by dilution with H₂ O. Afterwashing the aqueous phase 2× with 1:1 Et₂ O/hexane and thenacidification to pH 1 with 2.5N H₂ SO₄, the title compound was collectedby filtration as a white solid (8.6 g).

B. α-((4-Difluoromethoxy)phenyl)-4-fluorobenzene ethanamine

To a stirred suspension of Zn powder (3.3 g, 50 mmol) and Pd(PPh₃)₄(1.45 g, 1.25 mmol) in DME (20 mL) under N₂, was added 10 mL of DMEcontaining 4-fluorobenzyl bromide (4.9 g, 26 mmol) and4-difluoromethoxybenzoate chloride (4.7 g, 25 mmol) (prepared byrefluxing 4-difluoromethoxybenzoate acid in SOCl₂). After stirring 40hours at 20° C., the reaction was diluted with EtOAc and H₂ O, filteredthrough Celite, and then concentrated. The crude product was dissolvedin EtOAc, washed with brine, dried over Na₂ SO₄, and then concentratedto 10 g of crude product. Chromatography on silica gel using 1:2 CH₂ Cl₂/hexane eluted 4 g of1-((4-difiuoromethoxy)phenyl)-2-(4-fluorophenyl)ethanone. This washeated with about 10 equivalents of ammonium formate at about 170° C.for about one day before cooling, dilution with water, and extractionwith EtOAc several times. The combined extracts were dried over sodiumsulfate and evaporated to provide the N-formylated title compound. Thiswas heated at 90° C. in a sealed tube with about a 1:1 mixture ofmethanol and conc. aq. HCl for several hours. After cooling to roomtemperature, the mixture was diluted with water and washed twice withEt20 before basification with aq. NaOH solution. This was extractedseveral times with EtOAc, and the combined extracts were dried oversodium sulfate and evaporated. After pretreatment with excess TFA, thetitle amine was purified fromα-(4-hydroxyphenyl)-4-fluorobenzeneethanamine by preparative HPLCchromatography using a C₁₈ HPLC column eluting with 50% solvent B(solvent A=10% MeOH, 90% H₂ O, 0.1% TFA; solvent B=90% MeOH, 10% H₂ O,0.1% TFA), followed by liberation from the TFA salt by standardprocedures.

C.(2S)-1-[[1-[4-(Difluoromethoxy)phenyl]-2-(4-fluorophenyl)ethyl]amino]-3-phenoxy-2-propanol,monohydorchloride

Under argon a mixture of the title A compound of Example 1((S)-(phenoxymethyl)oxirane; optical purity of 99.2% ee; 0.08 g, 0.53mmol) and impure title B compound (about 85% pure, 0.17 g net, 0.61mmol) was heated to 135° C. and stirred for 2.5 hours. After cooling toroom temperature the mixture was flash chromatographed (silica gel, 0.5%to 0.8% [10% conc. aq. NH₃ /MeOH]/CH₂ Cl₂ stepwise gradient) to providethe free base of the title compound as an oil. A solution of the freebase in diethyl ether was prepared, and HCl gas was passed over thesolution, but the mixture remained homogeneous. Addition of hexanecaused an oil to form. The supernatant was removed, and the oil wasdissolved in methanol. This solution was diluted with water, andpartially evaporated to remove most of the methanol. Lyophilization gavethe title compound (0.07 g, 30% yield) as a fluffy material that latercollapsed into a gum.

TLC (2.5% [10% conc. aq. NH₃ in MeOI-I]in CH₂ Cl₂ -anisaldehyde, UV)R_(f) : (S)-(phenoxymethyl)oxirane 0.86 the title B compound 0.16 thetitle compound 0.27

MS by chemical ionization: (M+H)⁺ @432.

EXAMPLE 16(2S)-1-[[1-[4-(Methylsulfonyl)phenyl]-2-phenylethyl]amino]-3-phenoxy-2-propanot,monohydrochloride ##STR40## A. α-[4-(Methylthio)phenyl]benzeneethanol

To 50 mL of 2.0M benzylmagnesium chloride in THF solution (100 mmol)stirring under argon at 48° C. was added over 10 minutes a solution of13.9 g of 4-methylthiobenzaidehyde (91 mmol) in 15 mL of fleshlydistilled THF. Exotherm caused the mixture to reflux. For 25 minutesafter the addition was complete reflux was maintained with furtherheating. The homogeneous mixture was cooled to room temperature, andwhile stirring, 30 mL of sat. aq. ammonium chloride solution (about 2equiv.) was added. This addition was also exothermic and resulted in theformation of a paste plus supernatant. The supernatant was decanted, andseveral times the paste was stirred with additional THF and thesupernatant removed. The combined supernatants were diluted withtoluene, dried over sodium sulfate, and evaporated. This provided 22.7 gof 90% pure title compound as a yellow solid (20.4 g net, 92% yield).

TLC (25% EtOAc in hexane-anisaldehyde, UV) R_(f) :4-methylthiobenzaldehyde 0.50 the title compound 0.38

¹³ C NMR (6,8Mitz, CDCl₁₃): δ140.7, 137.8, 137.5, 129.4, 128.5, 126.6,126.4, 74.8, 45.9, 15.9.

B. α-[4-(Methylsulfonyl)phenyl]benzeneethanol

A solution of the title A compound (15.8 g, 90% pure, 14.2 g net, 58mmol) in 300 mL methylene chloride was stirred at 0° C. with a pH 8solution of K₂ HPO₄ (42 g, 240 mmol) and KH₂ PO₄ (5.0 g, 37 mmol) in 500mL of water. To this mixture was added 15 g of 75% mCPBA (11 g net, 65mmol). TLC at five minutes indicated that much of the starting materialhad been converted to a very low R_(f) material (putative sulfoxide).Addition of 27 g more oxidant (20 g net, 117 mmol) caused the formationof white precipitate, and TLC after 15 minutes indicated completeconsumption of starting material and disappearance of putative sulfoxidewith the formation of the title compound. The aqueous layer wasseparated, and the organic layer was filtered. The filtrate was washedsequentially with 200 mL of 1.0M aq. Na₂ S₂ O₃, 200 mL of 1.0M aq.sodium bicarbonate, and 200 mL of 1.0M aq. NaOH. After drying oversodium sulfate and solvent evaporation, 17.4 g of 90% pure titlecompound (15.7 g net, 98% yield) was obtained as an off-white solid.

TLC (50% EtOAc in hexane-anisaldehyde, UV) R_(f) : the title A compound0.80 putative sulfoxide 0.05 the title B compound 0.36

MS by chemical ionization: (M+NH₄)⁺ @294.

¹³ C NMR (68 MHz, CDCl₃): δ150.2, 139.1, 137.0, 129.4, 128.5, 127.2,126.8, 74.2, 45.8, 44.3.

C. 1-[4-(Methylsulfonyl)phenyl]-2-phenyl-1-ethanone

A solution of the title B compound (10.5 g, 90% pure, 9.5 g net, 34mmol) in 100 mL acetone was stirred at 0° C. under argon as Jones'reagent was slowly added until a red-orange color persisted (12 mL).Blue-green precipitate formed. Excess oxidant was quenched with2-propanol after 15 minutes. Ethyl acetate and 3M aq. sodium bisulfitewere added, and the mixture was stirred at room temperature until allsolids had dissolved. This was extracted with ethyl acetate four times,and the combined extracts, diluted with methylene chloride, were driedover sodium sulfate and evaporated. This provided 10.0 g of 85% puretitle compound (8.5 g net, 91% yield) as a wet white solid.

TLC (50% EtOAc in hexane-anisaldehyde, UV) R_(f) : the title B compound0.33 the title C compound 0.48k

¹³ C NMR (68 MHz, CD₃ SOCD₃): δ197.2, 144.3, 140.1, 134.5, 129.8, 129.2,128.4, 127.4, 126.6, 45.1, 43.2.

D. N-[1-[4-(Methylsulfonyl)phenyl]-2-phenylethyl]-formamide

A mixture of the title C compound (5.5 g, 85% pure, 4.6 g net, 17 mmol)and ammonium formate (12.6 g, 200 retool) was heated to 180° C. withstirring for four hours. The mixture, which eventually becamehomogeneous, was cooled before addition of water and ethyl acetate. Awhite precipitate was produced. The mixture was extracted four timeswith ethyl acetate and four times with methylene chloride. The mixturestill contained precipitate, which was filtered, water washed, andair-dried to provide 0.48 g of pure title compound (9% yield) as a whitesolid. The combined extracts were dried over sodium sulfate andevaporated to provide 6.72 g of impure title compound (66% pure, 4.43 gnet, 86% yield) for a total yield of 95%.

TLC (50% EtOAc in hexane--anisaldehyde, UV) R_(f) : the title C compound0.57 the title D compound 0.06

MS by chemical ionization: (M+NH₄)⁺ @321 and (M+H)⁺ @304.

E. α-[4-(Methylsulfonyl)phenyl]benzeneethanamine

A sealed tube containing a mixture of 25 mL each of methanol and conc.aq. HCl and 2.05 g of impure title D compound (1.61 g net, 5.3 mmol) wasone third immersed in a 60° C. oil bath for four hours. Solid title Dcompound dissolved with stirring. The mixture was cooled to 0° C., andwas poured into 450 mL of 1.0M aq. NaOH stirring at 0° C. An oil formedand was extracted with methylene chloride (three times). The combinedextracts were dried over sodium sulfate and evaporated. This provided1.38 g of pure title compound (95% yield) as a pale yellow solid.

TLC (100% EtOAc- anisaldehyde, UV) R_(f) ; the title D compound 0.47 thetitle E compound 0.11

¹ H NMR (270 MHz, CDCl₃): δ1.51 (bs, 2H), 2.81 (dd, J=8, 13 Hz, 1H),2.98 (dd, J=5, 13 Hz, 1H), 3.04 (s, 3H), 4.30 (dd, J=5,8 Hz, 1H),7.10-7.35 (m, 5H), 7.55 (d, J: 8 Hz, 2H), 7.87 (d, J=8 Hz, 2H).

¹³ C NMR (68 MHz, CDCl₃): δ151.9, 138.9, 137.9, 129.1, 128.4, 127.4,127.3, 126.6, 57.0, 46.2, 44.4.

F.(2S)-1-[[1-[4-(Methylsulfonyl)phenyl]-2-phenylethyl]amino]-3-phenoxy-2-propanol,monohydrochloride

Under argon a mixture of the title A compound of Example 1((S)-(phenoxymethyl)oxirane; optical purity of 99.2% ee; 0.07 g, 0.47mmol) and the title E compound (0.16 g, 0.58 mmol) was heated to 135° C.and stirred for 2.5 hours. After cooling to room temperature the mixturewas flash chromatographed (silica gel, 1.0% to 1.5% [10% conc. aq.NH_(3/) MeOH]/CH₂ Cl₂ stepwise gradient) to provide the free base of thetitle compound as an oil. A solution of the free base in diethyl etherwas prepared, and HCl gas was passed over the solution until solidprecipitate stopped forming at the surface. The solid was filtered,washing with ether. After drying under vacuum, the title compound wasobtained as an off-white solid (95% pure, containing 3% diethyl ether,0.17 g, 0.16 g net, 74% yield).

TLC (2.5% [10% conc. aq. NH₃ in MeOH]in CH₂ Cl₂ -anisaldehyde, UV) R_(f): (S)-(phenoxymethyl)oxirane 0.88 the title E compound 0.10 the titlecompound 0.19

MS by electrospray ionization: (M+H)⁺ @426.

EXAMPLE 17[S-(R*,S*)]-1-[[1-(1,3-Benzodioxol-5-yl)-2-phenylethyl]amino]-3-phenoxy-2-propanol##STR41## A.(R,E)-β-[[(1,3-Benzodioxol-5-yl)methylene]amino]benzeneethanol

To piperonal (m.w. 150, 12.0 g, 80.0 mmol) in CDCl₃ (40 mL) was added(R)-phenylglycinol (Aldrich, m.w. 137, 11.0 g, 80.0 mmol, 1.0 equiv.).The ee of the phenylglycinol was shown to be 98.7% by chiral HPLCanalysis. The solution was stirred at room temperature overnight, thenwith a few grams of sodium sulfate. The mixture was filtered andcoevaporated several times with toluene and then several times withmethylene chloride to provide the title compound as a yellow oil (21.41g, 99% yield).

B.[R-(R*,R*)]-β-[[1-(1,3-Benzodioxol-5-yl)-2-phenylethyl]amino]benzeneethanol,monohydrochloride

To THF (freshly distilled from potassium benzophenone ketyl, 300 mL) atroom temperature in an oven dried flask was added CeCl₃ (m.w. 246.5,60.0 g, 243 retool, 3.1 equiv., freshly opened). The mixture was stirredovernight at room temperature under argon. The mixture was chilled to-45° C. and then benzylmagnesium chloride (2.0M in THF, 120 mL, 240mmol, 3.0 equiv.) was added by cannula. This mixture was stirred at -45°C. for 1.5 hours. Then a solution of the title A compound (m.w. 269,21.2 g, 78.8 mmol) in THF (˜50 mL) was added over about 40 minutes. Themixture was allowed to warm to room temperature after 10 minutes moreand was then cautiously quenched by addition of 800 mL of water. Thiswas extracted three times with ˜600 mL of methylene chloride, and theextracts were dried (Na₂ SO₄) and concentrated to an oil which was shownby analytical HPLC to contain an 11:1 mixture of the title compound andits diastereomer. The oil was dissolved in 500 mL of ether. To the ethersolution was added a solution of methanolic HCl made by cautiousaddition of AcCl (m.w. 78, 12.5 g, 160 mmol, ˜2 equiv.) to ˜40 mL ofmethanol at 0° C. White precipitate formed immediately. The mixture waschilled at 0° C. and the precipitate was filtered and thenrecrystallized from ˜400 mL of MeOH and 1.5 L of ether. After chillingovernight at 0° C. the precipitate (pure title compound, 23.3 g, 74%yield) was collected by filtration, rinsed with ether, and dried undervacuum.

TLC (5% (10% conc. aq. NH₄ OH/MeOH)/CH₂ Cl₂): R_(f) =0.65, UV,p-anisaldehyde stain.

¹³ C NMR (67.8 MHz, CD₃ OD): δ150.2, 150.0, 136.9, 135.1, 130.9, 130.5,130.4, 129.6, 129.5, 128.8, 128.1, 124.4, 109.6, 109.2, 103.1, 64.9,63.5, 63.3, 40.1.

HPLC: YMC ODS S3 6.0×150 mm column, gradient elution with 0-100% B(A=90% H₂ O, 10% MeOH, 0.2% H₃ PO₄, B=90% MeOH, 10% H₂ O, 0.2% H₃ PO₄)over 25 minutes, at a flow rate of 1.5 mL/minute with detection at 217nm, major diastereomer title compound elutes at 19.1 minutes, minordiastereomer elutes at 19.9 minutes.

C. (R)-α-(1,3-Benzodioxol-5-yl)benzeneethanamine

The title B compound (m.w. 398, 21.1 g, 53.1 retool) was partitionedbetween ˜150 mL of methylene chloride and ˜150 mL of 1M aq. NaHCO₃. Theorganic layer was removed and the aqueous layer was extracted twice morewith ˜150 mL of methylene chloride. The organic layers were combined,dried over sodium sulfate, and concentrated to a thick oil.

To 800 mL of MeOH at 0° C. under argon was added Pb(OAc)₄ (m.w. 443,30.6 g, 69.1 mmol, 1.3 equiv.). The free-based title B compound wasadded as a solution in 400 mL methylene chloride over a period of 30-40minutes. Soon afterward the yellow reaction solution was diluted with200 mL of methylene chloride and 10% aq. Na₂ CO₃ (600 mL) was added. Theorganic layer was removed and the aqueous layer extracted three timeswith 200 mL of CH₂ Cl₂. The various organic layers were combined, driedover Na₂ SO₄, and concentrated to a brown oil.

The oil was dissolved in a solution of 150 mL of water, 50 mL of MeOH,and 12 mL of conc. aq. HCl. After stirring at 60° C. for six hours, thereaction solution was cooled to room temperature and then basified to pH12 by addition of 1M aq. NaOH. The organic layer was removed and theaqueous layer was extracted 3 times with ˜200 mL of methylene chloride.The organic extracts were combined and dried over sodium sulfate andthen concentrated to a thick oil. The oil was dissolved in 500 mL ofether. To the ether solution was added a solution of methanolic HCl madeby cautious addition of AcCl (m.w. 78, 12.5 g, 160 mmol, ˜3 equiv.) to˜40 mL of methanol at 0° C. White precipitate formed immediately. Themixture was chilled at 0° C. and the precipitate was filtered. Afterdrying under vacuum the precipitate, pure HCl salt of the title compound(9.3 g, 63% yield), was partitioned between ˜150 mL of methylenechloride and ˜150 mL of 1M aq. NaHCO₃. The organic layer was removed andthe aqueous layer was extracted twice more with ˜150 mL of methylenechloride. The organic layers were combined, dried over sodium sulfate,and concentrated to afford as a brown solid (9.1 g) incompletelyfree-based amine. This material was Kugelrohr distilled at 0.06-0.08torr at 175°-190° C. to provide 5.6 g of clear, colorless oil. ChiralHPLC (GITC derivative, PGC column, MeCN/H₂ O 85:15 eluant) indicated theoptical purity of the title compound to be 95.1% ee.

TLC (10% (10% conc aq NH₄ OH/MeOH)/CH₂ Cl₂): R_(f) =0.8, UV,p-anisaldehyde stain.

¹³ C NMR (67.8 MHz, CDCl₃): δ46.5, 57.2, 100.8, 106.7, 107.9, 119.4,126.2, 128.3, 129.2, 138.9, 139.7, 146.3, 147.5.

Elemental Analysis:

    ______________________________________                                                   Calculated                                                                            Found                                                      ______________________________________                                        C            74.67     74.81                                                  H            6.27      6.53                                                   N            5.80      5.87                                                   ______________________________________                                    

D.[S-(R*S*)]-1-[[1-(1,3-Benzodioxol-5-yl)-2-phenylethyl]amino]-3-phenoxy-2-propanol

In an oven-dried flask under argon a mixture of the title C compound(95.1% ee, 1.02 g, 4.23 mmol) and N-(trimethylsilyl)acetamide (0.63 g,4.81 mmol) was melted and stirred at 90° C. for one hour. To this wasadded the title A compound of Example I ((S)-(phenoxymethyl)oxirane;optical purity of 99.2% ee; 0.42 g, 2.80 mmol) and the homogeneousmixture was heated at 120° C. for 20 hours. After cooling to roomtemperature, about 40 mL each of EtOAc and 6M aq. HCl were added, andafter stirring for about 10 minutes, a homogeneous mixture had formed.After two to four hours addition of several volumes of EtOAc produced amixture of two layers. Aq. NaOH (1.0M) was added until the mixture wasbasic. Ice was added to cool the mixture and the organic layer wasseparated. Another extraction with EtOAc was performed, and the combinedorganic layers diluted with methylene chloride were dried over anhydroussodium sulfate and evaporated. Flash chromatography (silica gel, 25% to40% EtOAc in hexane) provided pure title compound (0.99 g, 90% yield) asa white solid.

TLC (5% [10% conc. aq. NH₃ in MeOH] in CH₂ Cl₂ -anisaldehyde, UV) R_(f): the title C compound 0.28 (S)-(phenoxymethyl)oxirane 0.93 silylatedtitle compound intermediate 0.93 the title compound 0.39

MS by electrospray ionization: (M+H)⁺ @392.

¹ H NMR (270 MHz, CDCl₃): δ2.5-2.7 (m, 2H), 2.8-3.0 (m, 2H), 3.7-3.9 (m,4H), 5.91 (bs, 2H), 6.6-7.0 (m, 6H), 7.1-7.3 (m, 7H).

¹³ C NMR (67.8 MHz, CDCl₃): δ158.5, 147.8, 146.6, 138.5, 137.5, 129.4,129.2, 128.4, 126.4, 120.9, 120.5, 114.4, 107.9, 107.1, 100.8, 70.4,68.8, 64.9, 49.7, 45.2.

EXAMPLE 18[S-R*,R*)]-1-[[1-(1,3-Benzodioxol-5-yl)-2-phenylethyl]amino]-3-phenoxy-2-propanol,trifluoroacetate (1:1) ##STR42## A. [R-(R*S*)]-β-[[1-(1,3-Benzodioxol-5-yl)-2-phenylethyl]amino]benzeneethanol,trifluoroacetate

The HCl salt of the title compound was contained within the motherliquors from the preparation of the title B compound of Example 17 asthe minor diastereomer. This material was purified (and changed to theTFA salt) by preparative HPLC (YMC SC-15 ODS S3 50×500 mm column,elution with 62% B (A=90% H₂ O, 10% MeOH, 0.8% TFA, B=90% MeOH, 10% H₂O, 0.8% TFA), at a flow rate of 60 mL/minute).

¹³ C NMR (67.8 MHz, CD₃ OD): δ150, 136.6, 133.5, 131.0, 130.5, 130.2,129.5, 128.1, 128.0, 124.4, 109.4, 108.8, 103.1, 64.1, 40.9.

B. (S)-α-(1,3-Benzodioxol-5-yl)benzeneethanamine

This procedure is essentially the same as that used for the preparationof the title C compound of Example 17 with the following modifications:In the various extractions, Et₂ O was sometimes substituted formethylene chloride and aq. NaOH was sometimes substituted for aq.NaHCO₃. Also, the title compound was not distilled. Chiral I-tPLC (GITCderivative, PGC column, MeCN/H₂ O 85:15 eluant) indicated the opticalpurity of the title compound was 99.4% ee.

C.[S-R*,R*)]-1-[[1-(1,3-Benzodioxol-5-yl)-2-phenylethyl]amino]-3mino]-3-phenoxy-2-propanol,trifluoroacetate (1:1)

This step was carried out as in step D of Example 17 except that thereaction was worked up prior to completion, the yield was 70%, and theproduct free base was an oil. The oil was dissolved in CH₂ Cl₂. ExcessTFA was added, and the solution was evaporated. Coevaporation withtoluene, then CH₂ Cl₂, then Et₂ O gave the title compound as a solidfoam.

TLC (5% [10% conc. aq. NH₃ in MeOH] in CH₂ Cl₂ -anisaldehyde, UV) R_(f): the title B compound 0.22 (S)-(phenoxymethyl)oxirane 0.94 silylatedtitle compound intermediate 0.94 the title compound 0.33

MS by electrospray ionization: (M+H)⁺ @392.

¹ H NMR (270 MHz, CD₃ OD): δ2.87 (dd, J=10, 12 Hz, 1H), 3.15-3.25 (m,2H), 3.46 (dd, J=4, 13 Hz, 1H), 3.80-4.0 (m, 2H), 4.27 (m, 1H), 4.46(dd, J=4.7, 11.1 Hz, 1H), 5.95 (m, 2H), 6.7-7.3 (m, 13H).

13C NMR (68 MHz, CD₃ OD): δ159.7, 150.1, 150.0, 136.7,130.5, 130.4,129.6, 128.2, 128.1, 124.3, 122.3, 115.6, 109,5, 108.9, 103.0, 70.7,66.5, 65.4, 49, 40.6.

EXAMPLE 19 [S-(R* S*)]4-[3-[[1-(1,3-Benzodioxol-5-yl)-2-phenylethyl]amino]-2-hydroxypropoxy]-1H-benzimidazol-2(3H)-one ##STR43## A.[S-(R*,S*)]-1-(2-Amino-3-nitrophenoxy)-3-[[1-(1,3-benzodioxol-5-yl)-2-phenylethyl]amino]-2-propanol

This step was performed as described for the analogous step in Example10, starting with the title C compound of Example 17 and the title Acompound of Example 10 (the Example 10A compound used here was preparedby the Aigbirhio method (2-amino-3-nitrophenol, (2S)-(+)-glycidyl3-nitrobenzenesulfonate (99.8% ee), potassium carbonate, 2butanone,reflux) which gave the title compound in 44% yield at 90.4% ee), exceptthat during acidic hydrolysis of the silylated intermediate the mixturenever became homogeneous even when heated. Flash chromatography (silicagel, 25% to 100% EtOAc in hexane stepwise gradient) provided the titlecompound in 92% yield as an orange foam.

TLC (5% [10% cone. aq. NH₃ in MeOH]in CH₂ Cl₂ -anisaldehyde, UV) R_(f) :the title C compound of Example 17 0.22 the title A compound of Example10 0.82 silylated title compound intermediate 0.90 the title compound0.31

¹ H NMR (270 MHz, CDCl₃): δ2.5-2.7 (m, 2H), 2.8-3.0 (m, 2H), 3.76 (m,1H), 3.8-4.0 (m, 3H), 5.92 (s, 2H), 6.42 (bs, 2H), 6.51 (m, 1H), 6.6-6.9(m, 4H), 7.1-7.3 (m, 5H), 7.69 (dd, J=1.2, 8.8 Hz, 1H).

¹³ C NMR (68 MHz, CDCl₃): δ147.8, 147.1, 146.7, 138.4, 137.3, 137.2,131.5, 129.1, 128.3, 126.4, 120.4, 117.8, 115.4, 114.4, 108.0, 106.9,100.9, 71.7, 68.7, 65.0, 49.6, 44.9.

[S-(R*,S*)]-4-[3-[[1-(1,3-Benzodioxol-5-yl)-2-phenylethyl]amino]-2-hydroxypropoxy]-1H-benzimidazol-2(3H)-one

The title compound was prepared from the title A compound following theprocedures described in Examples 11 and 12 with the followingmodifications: The catalytic hydrogenation step was run for a longertime (16 hours) and using more 50% Raney Nickel/water slurry (3 g pergram of title A compound). The free base of the diaminobenzeneintermediate was not isolated. Rather, after filtration through silicagel in THF, the eluant was acidified by addition of 1.0M aq. HCl. Thissolution was concentrated to a small volume, diluted with water, andagain concentrated to a small volume. The resulting brown solution wasfiltered through Celite to remove a small amount of brown precipitate.The filtrate was then treated with phosgene as described in Example 12.However, during the work-up, basification was performed with aq. NaOH(to pH 11) and extractions were with methylene chloride alone. Flashchromatography (silica gel, 2% to 4% [10% cone. aq. NH₃ in MeOH]in CH₂Cl₂, stepwise gradient), followed by trituration with diethyl ether andevaporation, provided the title compound as a tan solid in 84% yield.

TLC (10% [10% cone. aq. NH₃ in MeOH]in CH₂ Cl₂ -anisaldehyde, UV) R_(f): the title A compound 0.54 diaminobenzene intermediate 0.34 the titlecompound 0.29

MS by chemical ionization: (M+H)⁺ @448 and (M-H)-@446.

¹ H NMR (270 MHz, CD₃ OD): δ2.45-2.65 (m, 2H), 2.8-3.0 (m, 2H), 3.79 (t,J=7.0 Hz, 1H), 3.85-4.05 (m, 3H), 5.88 (m, 2H), 6.55-6.7 (m, 4H), 6.84(s, 1H), 6.93 (t, J=8.2 Hz, 1H), 7.05-7.25 (m, 5H). ¹³ C NMR (68 MHz,CD₃ OD): δ157.7, 149.3, 148.1, 144.7, 139.9, 138.0, 131.8, 130.3, 129.3,127.4, 123.0, 122.2, 120.0, 108.8, 108.4, 106.3, 104.1, 102.2, 72.0,70.2, 66.5, 50.9, 45.6.

Using the procedures described herein or by modification of theprocedures described herein as known by the skilled artisan, thefollowing additional compounds may be prepared. For all divalentsubstituents listed below, the two points of attachment on the divalentsubstituent are shown in the same order as the positions to which theyare attached. For example, in Example 23, the carbon atom is attached tothe ortho position and the nitrogen atom is attached to the metaposition.

    __________________________________________________________________________    Example #                                                                           R.sub.1 R.sub.2                                                                           R.sub.3                                                                           R.sub.4                                                                             R.sub.5                                                                              R.sub.6                                                                            R.sub.7                                                                         R.sub.8                                                                         R.sub.9                                                                         m                               __________________________________________________________________________    20    m-CH.sub.2 OH                                                                         H   H   p-MeO m-MeO  H    H H H 1                               21    m-CH.sub.3 SO.sub.2 NH                                                                H   H   p-MeO m-MeO  H    H H H 1                               22    m-CH.sub.3 SO.sub.2 NH                                                                p-OH                                                                              H   p-MeO m-MeO  H    H H H 1                               23    o,m-C(CN)═CHNH                                                                        H   p-MeO m-MeO  H    H H H 1                               24    o,m-OCONH   H   p-MeO m-MeO  H    H H H 1                               25    o,m-NHCONH  p-OH                                                                              p-MeO m-MeO  H    H H H 1                               26    o,m-CH═CHCONH                                                                         H   p-MeO m-MeO  H    H H H 1                               27    o,m-CH═CHCONH                                                                         p-OH                                                                              p-MeO m-MeO  H    H H H 1                               28    o,m-N═NNH                                                                             p-OH                                                                              p-MeO m-MeO  H    H H H 1                               29    p-OH    m-OH                                                                              H   p-MeO m-MeO  H    H H H 1                               30    m-CH.sub.3 SO.sub.2 NH                                                                H   H   m,p-OCH.sub.2 O                                                                            H    H H H 1                               31    m-CH.sub.3 SO.sub.2 NH                                                                p-OH                                                                              H   m,p-OCH.sub.2 O                                                                            H    H H H 1                               32    o,m-C(CN)═CHNH                                                                        H   m,p-OCH.sub.2 O                                                                            H    H H H 1                               33    o,m-OCONH   H   m,p-OCH.sub.2 O                                                                            H    H H H 1                               34    o,m-NHCONH  p-OH                                                                              m,p-OCH.sub.2 O                                                                            H    H H H 1                               35    o,m-CH═CHCONH                                                                         H   m,p-OCH.sub.2 O                                                                            H    H H H 1                               36    o,m-CH═CHCONH                                                                         p-OH                                                                              m,p-OCH.sub.2 O                                                                            H    H H H 1                               37    o,m-N═NNH                                                                             H   m,p-OCH.sub.2 O                                                                            H    H H H 1                               38    o,m-N═NNH                                                                             p-OH                                                                              m,p-OCH.sub.2 O                                                                            H    H H H 1                               39    m-OH    H   H   m,p-OCH.sub.2 O                                                                            H    H H H 1                               40    p-OH    H   H   m,p-OCH.sub.2 O                                                                            H    H H H 1                               41    p-OH    m-OH                                                                              H   m,p-CCH.sub.2 O                                                                            H    H H H 1                               42    m-CH.sub.2 OH                                                                         H   H   m,p-OCH.sub.2 O                                                                            H    H H H 1                               43    m-CH.sub.3 SO.sub.2 NH                                                                H   H   p-MeO H      H    H H H 1                               44    m-CH.sub.3 SO.sub.2 NH                                                                p-OH                                                                              H   p-MeO H      H    H H H 1                               45    o,m-C(CN)═CHNH                                                                        H   p-MeO H      H    H H H 1                               46    o,m-OCONH   H   p-MeO H      H    H H H 1                               47    o,m-NHCONH  H   p-MeO H      H    H H H 1                               48    o,m-NHCONH  p-OH                                                                              p-MeO H      H    H H H 1                               49    o,m-CH═CHCONH                                                                         H   p-MeO H      H    H H H 1                               50    o,m-CH═CHCONH                                                                         p-OH                                                                              p-MeO H      H    H H H 1                               51    o,m-N═NNH                                                                             H   p-MeO H      H    H H H 1                               52    o,m-N═NNH                                                                             p-OH                                                                              p-MeO H      H    H H H 1                               53    m-OH    H   H   p-MeO H      H    H H H 1                               54    p-OH    H   H   p-MeO H      H    H H H 1                               55    p-OH    m-OH                                                                              H   p-MeO H      H    H H H 1                               56    m-CH.sub.2 OH                                                                         H   H   p-MeO H      H    H H H 1                               57    H       H   H   p-MeO H      H    H H H 1                               58    m-CH.sub.3 SO.sub.2 NH                                                                H   H   m-MeO H      H    H H H 1                               59    m-CH.sub.3 SO.sub.2 NH                                                                p-OH                                                                              H   m-MeO H      H    H H H 1                               60    o,m-C(CN)═CHNH                                                                        H   m-MeO H      H    H H H 1                               61    o,m-OCONH   H   m-MeO H      H    H H H 1                               62    o,m-NHCONH  H   m-MeO H      H    H H H 1                               63    o,m-NHCONH  p-OH                                                                              m-MeO H      H    H H H 1                               64    o,m-CH═CHCONH                                                                         H   m-MeO H      H    H H H 1                               65    o,m-CH═CHCONH                                                                         p-OH                                                                              m-MeO H      H    H H H 1                               66    o,m-N═NNH                                                                             H   m-MeO H      H    H H H 1                               67    o,m-N═NNH                                                                             p-OH                                                                              m-MeO H      H    H H H 1                               68    m-OH    H   H   m-MeO H      H    H H H 1                               69    p-OH    H   H   m-MeO H      H    H H H 1                               70    p-OH    m-OH                                                                              H   m-MeO H      H    H H H 1                               71    m-CH.sub.2 OH                                                                         H   H   m-MeO H      H    H H H 1                               72    H       H   H   m-MeO H      H    H H H 1                               73    m-CH.sub.3 SO.sub.2 NH                                                                H   H   p-CF.sub.2 HO                                                                       H      H    H H H 1                               74    m-CH.sub.3 SO.sub.2 NH                                                                p-OH                                                                              H   p-CF.sub.2 HO                                                                       H      H    H H H 1                               75    o,m-C(CN)═CHNH                                                                        H   p-CF.sub.2 HO                                                                       H      H    H H H 1                               76    o,m-OCONH   H   p-CF.sub.2 HO                                                                       H      H    H H H 1                               77    o,m-NHCONH  H   p-CF.sub.2 HO                                                                       H      H    H H H 1                               78    o,m-NHCONH  p-OH                                                                              p-CF.sub.2 HO                                                                       H      H    H H H 1                               79    o,m-CH═CHCONH                                                                         H   p-CF.sub.2 HO                                                                       H      H    H H H 1                               80    o,m-CH═CHCONH                                                                         p-OH                                                                              p-CF.sub.2 HO                                                                       H      H    H H H 1                               81    o,m-N═NNH                                                                             H   p-CF.sub.2 HO                                                                       H      H    H H H 1                               82    o,m-N═NNH                                                                             p-OH                                                                              p-CF.sub.2 HO                                                                       H      H    H H H 1                               83    m-OH    H   H   p-CF.sub.2 HO                                                                       H      H    H H H 1                               84    p-OH    H   H   p-CF.sub.2 HO                                                                       H      H    H H H 1                               85    p-OH    m-OH                                                                              H   p-CF.sub.2 HO                                                                       H      H    H H H 1                               86    m-CH.sub.2 OH                                                                         H   H   p-CF.sub.2 HO                                                                       H      H    H H H 1                               87    H       H   H   p-CF.sub.2 HO                                                                       H      H    H H H 1                               88    m-CH.sub.3 SO.sub.2 NH                                                                H   H   p-CONH.sub.2                                                                        H      H    H H H 1                               89    m-CH.sub.3 SO.sub.2 NH                                                                p-OH                                                                              H   p-CONH.sub.2                                                                        H      H    H H H 1                               90    o,m-C(CN)═CHNH                                                                        H   p-CONH.sub.2                                                                        H      H    H H H 1                               91    o,m-OCONH   H   p-CONH.sub.2                                                                        H      H    H H H 1                               92    o,m-NHCONH  H   p-CONH.sub.2                                                                        H      H    H H H 1                               93    o,m-NHCONH  p-OH                                                                              p-CONH.sub.2                                                                        H      H    H H H 1                               94    o,m-CH═CHCONH                                                                         H   p-CONH.sub.2                                                                        H      H    H H H 1                               95    o,m-CH═CHCONH                                                                         p-OH                                                                              p-CONH.sub.2                                                                        H      H    H H H 1                               96    o,m-N═NNH                                                                             H   p-CONH.sub.2                                                                        H      H    H H H 1                               97    o,m-N═NNH                                                                             p-OH                                                                              p-CONH.sub.2                                                                        H      H    H H H 1                               98    m-OH    H   H   p-CONH.sub.2                                                                        H      H    H H H 1                               99    p-OH    H   H   p-CONH.sub.2                                                                        H      H    H H H 1                               100   p-OH    m-OH                                                                              H   p-CONH.sub.2                                                                        H      H    H H H 1                               101   m-CH.sub.2 OH                                                                         H   H   p-CONH.sub.2                                                                        H      H    H H H 1                               102   H       H   H   p-CONH.sub.2                                                                        H      H    H H H 1                               103   m-CH.sub.3 SO.sub.2 NH                                                                H   H   p-MeO o,m-CH═CHCH═CH                                                                    H H H 1                               104   m-CH.sub.3 SO.sub.2 NH                                                                p-OH                                                                              H   p-MeO o,m-CH═CHCH═CH                                                                    H H H 1                               105   o,m-C(CN)═CHNH                                                                        H   p-MeO o,m-CH═CHCH═CH                                                                    H H H 1                               106   o,m-OCONH   H   p-MeO o,m-CH═CHCH═CH                                                                    H H H 1                               107   o,m-NHCONH  H   p-MeO o,m-CH═CHCH═CH                                                                    H H H 1                               108   o,m-NHCONH  p-OH                                                                              p-MeO o,m-CH═CHCH═CH                                                                    H H H 1                               109   o,m-CH═CHCONH                                                                         H   p-MeO o,m-CH═CHCH═CH                                                                    H H H 1                               110   o,m-CH═CHCONH                                                                         p-OH                                                                              p-MeO o,m-CH═CHCH═CH                                                                    H H H 1                               111   o,m-N═NNH                                                                             H   p-MeO o,m-CH═CHCH═CH                                                                    H H H 1                               112   o,m-N═NNH                                                                             p-OH                                                                              p-MeO o,m-CH═CHCH═CH                                                                    H H H 1                               113   m-OH    H   H   p-MeO o,m-CH═CHCH═CH                                                                    H H H 1                               114   p-OH    H   H   p-MeO o,m-CH═CHCH═CH                                                                    H H H 1                               115   p-OH    m-OH                                                                              H   p-MeO o,m-CH═CHCH═CH                                                                    H H H 1                               116   m-CH.sub.2 OH                                                                         H   H   p-MeO o,m-CH═CHCH═CH                                                                    H H H 1                               117   H       H   H   p-MeO o,m-CH═CHCH═CH                                                                    H H H 1                               __________________________________________________________________________

What is claimed is:
 1. A compound of the formula ##STR44## orpharmaceutically acceptable salts thereof where R¹ is hydrogen, hydroxy,alkoxy, nitro, amino, alkylsulfonylamino, acylamino, alkylsulfonyl,alkyl, cycloalkyl, phenyl, hydroxymethyl, cyano, aminocarbonyl, halogenor trifluoromethyl;R² and R³ together with the carbon atoms to whichthey are attached, form a heterocycle; R⁴, R⁵ and R⁶ are independentlyhydrogen, alkoxycarbonyl, carboxy, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkoxycarbonylmethyl, carboxymethyl,aminocarbonylmethyl, alkylaminocarbonylmethyl,dialkylaminocarbonylmethyl, hydroxy, alkoxy, di- or trifluoromethoxy,halogen, trifluoromethyl, cycloalkyl or alkyl; or two of the threesubstituents (R⁴, R⁵ and R⁶) may together be methylenedioxy or benzosuch that they together with the benzene ring to which they are attachedform naphthyl; R⁷, R⁸ and R⁹ are independently hydrogen, alkoxycarbonyl,carboxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkoxycarbonylmethyl, carboxymethyl, aminocarbonylmethyl,alkylaminocarbonylmethyl, dialkylaminocarbonylmethyl, hydroxy, alkoxy,di- or trifluoromethoxy, halogen, trifluoromethyl, cycloalkyl or alkyl;or two of the three substituents (R⁷, R⁸ and R⁹) may together bemethylenedioxy or benzo such that they together with the benzene ring towhich they are attached form naphthyl; and m is the integer 0 or 1;provided that the heterocycle must be other than a 2-hydroxypyridine,2-oxopyridine, 3,4-dihydro-2-hydroxypyridine, 3,4-dihydro-2-oxopyridineor 2,1,3-benzothiadiazole.
 2. The compounds as recited in claim 1wherein the hydroxyl stereocenter has the (S) configuration.
 3. Thecompounds as recited in claim 1 wherein the hydroxyl stereocenter hasthe (S) configuration, the amine stereocenter has the (R) configurationand m is one.
 4. The compounds as recited in claim 1, whichare:(2S)-1-(1H-benzotriazol-5-yloxy)-3-[[1-(3,4-dimethoxyphenyl)-2-phenylethyl]amino]-2-propanol;(2S)-1,3-dihydro-4-[3-[[1-(3,4-dimethoxyphenyl)-2-phenylethyl]amino]-2-hydroxypropoxy]-2H-benzimidazol-2-one;(2S)-1-(1H-benzotriazol-4-yloxy)-3-[[1-(3,4-dimethoxyphenyl)-2-phenylethyl]amino]-2-propanol;[S-(R*,S*)]-4-[3-[[1-(1,3-benzodioxol-5-yl)-2-phenylethyl]amino]-2-hydroxypropoxy]-1H-benzimidazol-2(3H)-one;or a pharmaceutically acceptable salt thereof.
 5. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of the formula ##STR45## or pharmaceutically acceptable saltsthereof where R¹ is hydrogen, hydroxy, alkoxy, nitro, amino,alkylsulfonylamino, acylamino, alkylsulfonyl, alkyl, cycloalkyl, phenyl,hydroxymethyl, cyano, aminocarbonyl, halogen or trifluoromethyl;R² andR³ together with the carbon atoms to which they are attached, form aheterocycle; R⁴, R⁵ and R⁶ are independently hydrogen, alkoxycarbonyl,carboxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkoxycarbonylmethyl, carboxymethyl, aminocarbonylmethyl,alkylaminocarbonylmethyl, dialkylaminocarbonylmethyl, hydroxy, alkoxy,di- or trifluoromethoxy, halogen, trifluoromethyl, cycloalkyl or alkyl;or two of the three substituents (R⁴, R⁵ and R⁶) may together bemethylenedioxy or benzo such that they together with the benzene ring towhich they are attached form naphthyl; R⁷, R⁸ and R⁹ are independentlyhydrogen, alkoxycarbonyl, carboxy, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkoxycarbonylmethyl, carboxymethyl,aminocarbonylmethyl, alkylaminocarbonylmethyl,dialkylaminocarbonylmethyl, hydroxy, alkoxy, di- or trifluoromethoxy,halogen, trifluoromethyl, cycloalkyl or alkyl; or two of the threesubstituents (R⁷, R⁸ and R⁹) may together be methylenedioxy or benzosuch that they together with the benzene ring to which they are attachedform naphthyl; and m is the integer 0 or 1; provided that theheterocycle must be other than a 2-hydroxypyridine, 2-oxopyridine,3,4-dihydro-2-hydroxypyridine, 3,4-dihydro-2-oxopyridine or2,1,3-benzothiadiazole.
 6. A method for treating diabetes comprisingadministering to a mammalian specie in need thereof a therapeuticallyeffective amount of a composition of claim
 5. 7. A method for treatingobesity comprising administering to a mammalian specie in need thereof atherapeutically effective amount of a composition of claim
 5. 8. Amethod for treating intestinal hypermotility comprising administering toa mammalian specie in need thereof a therapeutically effective amount ofa composition of claim
 5. 9. A method for treating achalasia comprisingadministering to a mammalian specie in need thereof a therapeuticallyeffective amount of a composition of claim
 5. 10. A pharmaceuticalcomposition comprising a beta₁ or beta₂ adrenergic blocker or stimulant,a pharmaceutically acceptable carrier and a compound of formula##STR46## or pharmaceutically acceptable salts thereof where R¹ ishydrogen, hydroxy, alkoxy, nitro, amino, alkylsulfonylamino, acylamino,alkylsulfonyl, alkyl, cycloalkyl, phenyl, hydroxymethyl, cyano,aminocarbonyl, halogen or trifluoromethyl;R² and R³ together with thecarbon atoms to which they are attached, form a heterocycle; R⁴, R⁵ andR⁶ are independently hydrogen, alkoxycarbonyl, carboxy, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylmethyl,carboxymethyl, aminocarbonylmethyl, alkylaminocarbonylmethyl,dialkylaminocarbonylmethyl, hydroxy, alkoxy, di- or trifluoromethoxy,halogen, trifluoromethyl, cycloalkyl or alkyl; or two of the threesubstituents (R⁴, R⁵ and R⁶) may together be methylenedioxy or benzosuch that they together with the benzene ring to which they are attachedform naphthyl; R⁷, R⁸ and R⁹ are independently hydrogen, alkoxycarbonyl,carboxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkoxycarbonylmethyl, carboxymethyl, aminocarbonylmethyl,alkylaminocarbonylmethyl, dialkylaminocarbonylmethyl, hydroxy, alkoxy,di- or trifluoromethoxy, halogen, trifluoromethyl, cycloalkyl or alkyl;or two of the three substituents (R⁷, R⁸ and R⁹) may together bemethylenedioxy or benzo such that they together with the benzene ring towhich they are attached form naphthyl; and m is the integer 0 or 1;provided that the heterocycle must be other than a 2-hydroxypyridine,2-oxopyridine, 3,4-dihydro-2-hydroxypyridine, 3,4-dihydro-2-oxopyridineor 2,1,3-benzothiadiazole.
 11. A method for treating diabetes comprisingadministering to a mammalian specie in need thereof a therapeuticallyeffective amount of a composition of claim
 10. 12. A method for treatingobesity comprising administering to a mammalian specie in need thereof atherapeutically effective amount of a composition of claim
 10. 13. Amethod for treating intestinal hypermotility comprising administering toa mammalian specie in need thereof a therapeutically effective amount ofa composition of claim
 10. 14. A method for treating achalasiacomprising administering to a mammalian specie in need thereof atherapeutically effective amount of a composition of claim
 10. 15. Thecompounds of claim 2 where R¹, R⁴, R⁷ and R⁸ are hydrogen and m is one.16. The compounds of claim 2 where R¹, R⁴, R⁷, R⁸ and R⁹ are hydrogenand m is one.